CN114191424B - Pharmaceutical composition and application thereof in preparation of medicines for treating acute lung injury - Google Patents
Pharmaceutical composition and application thereof in preparation of medicines for treating acute lung injury Download PDFInfo
- Publication number
- CN114191424B CN114191424B CN202111372706.7A CN202111372706A CN114191424B CN 114191424 B CN114191424 B CN 114191424B CN 202111372706 A CN202111372706 A CN 202111372706A CN 114191424 B CN114191424 B CN 114191424B
- Authority
- CN
- China
- Prior art keywords
- lidocaine
- lung
- lung injury
- acute lung
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to the technical field of medicines, and particularly discloses a pharmaceutical composition and application thereof in preparing a medicine for treating acute lung injury. Compositions for treating acute lung injury include a compound and lidocaine. The pharmaceutical composition can reduce the death rate of animals with acute lung injury, wherein the combination of the compound and the lidocaine has a synergistic effect on reducing the lung coefficient, the lung permeability index, the release of inflammatory factors and the lung pathology score of the animals with acute lung injury.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a pharmaceutical composition and application thereof in preparing medicines for treating acute lung injury.
Background
Acute lung injury (acute lung injury, ALI) is a clinical syndrome that occurs due to pathological changes characteristic of the lung tissue structure that are caused by various causes. The pathological characteristics are that alveolar capillary endothelial cells and alveolar epithelial cells are damaged, and the injury is manifested as extensive pulmonary edema and tiny pulmonary atelectasis. Pathophysiological changes are mainly increased intra-pulmonary flow and decreased lung compliance. Clinically, hypoxia is manifested by respiratory rate and diffuse infiltration of the two lungs in X-ray chest film. ALI has a continuous process from light to heavy and currently lacks effective drugs and methods for treating acute lung injury.
Chinese patent document CN111514137a discloses a compound useful for treating acute lung injury, which can effectively reduce mortality caused by acute lung injury and restore normal lung function, and the therapeutic effect of the compound is equivalent to dexamethasone acetate. Lidocaine (2- (diethylamino) -N- (2, 6-dimethylphenyl) acetamide, CAS:137-58-6, lidocaine, LDC) is a common local anesthetic that can be used for local analgesia.
There is no report of the combination of compound LH031 with lidocaine for the treatment of acute lung injury.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a pharmaceutical composition and application thereof in preparing medicines for treating acute lung injury. The pharmaceutical composition can reduce the death rate of animals with acute lung injury, wherein the combination of the compound and the lidocaine has a synergistic effect on reducing the lung coefficient, the lung permeability index and the release of inflammatory factors of the animals with acute lung injury.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the present invention provides a composition for treating acute lung injury, the composition comprising a compound and lidocaine; the structural formula of the compound is shown as a formula (I):
the composition of the invention comprises a compound (LH 031, hereinafter expressed by the code) shown in the structural formula (I) and lidocaine, wherein the LH031 and the lidocaine can be used in combination to effectively treat acute lung injury, and the mortality is 1) obtained through experimental detection: compared with a model control group, a single LH031 group and a single lidocaine group, the combined treatment of LH031 and lidocaine has the curative effect of obviously reducing the death rate of animals with acute lung injury. 2) Lung coefficient and lung permeability index determination: the combination of LH031 and lidocaine is significantly better than the single LH031 group or the single lidocaine group, which shows that the combination of LH031 and lidocaine has a synergistic effect on reducing the lung coefficient and lung permeability index of rats with acute lung injury. 3) Detection of index in blood: LH031 in combination with lidocaine has a synergistic effect in reducing the release of inflammatory factors (IL-1. Beta., TNF-. Alpha., IL-6) in rats with acute lung injury. 4) Pathological morphology observation of lung tissue: the reduction of the lung pathology score of the animals combined by LH031 and lidocaine is obviously reduced, and the animal combined by LH031 and lidocaine has obvious statistical significance, which proves that the combined combination of LH031 and lidocaine has a synergistic effect on the improvement of the lung pathology score of rats.
As a preferred embodiment of the composition of the present invention, the dosage of the compound is 1mg/kg to 40mg/kg.
More preferably, the dose of the compound is 2mg/kg.
As a preferred embodiment of the composition of the present invention, the lidocaine concentration is 0.01% -0.1%.
More preferably, the lidocaine concentration is 0.1%.
The invention also provides application of the composition in preparation of a medicament for treating acute lung injury.
As a preferred embodiment of the use according to the invention, the medicament is in the form of an oral or injectable preparation.
As a preferred embodiment of the use according to the invention, the composition may reduce lung factor, lung permeability index, inflammatory factors and lung pathology scores.
As a preferred embodiment of the use according to the invention, the inflammatory factors include IL-1. Beta., TNF-. Alpha.and IL-6.
The invention discovers that the pharmaceutical composition can reduce the death rate of animals with acute lung injury, can also reduce the lung coefficient, the lung permeability index and the release of inflammatory factors of animals with acute lung injury, and can obviously improve the pathological morphology of lung tissues of animals with acute lung injury, so that the pharmaceutical composition has obvious treatment effect on acute lung injury, and the effect is superior or not inferior to that of the existing treatment drugs. The medicine composition of the invention can be prepared into oral preparations or injection, and the administration is simpler and more convenient.
Drawings
FIG. 1 is a structural formula of LH 031;
FIG. 2 is a structural formula of lidocaine;
FIG. 3 is a graph showing the effect of LH031 in combination with lidocaine on the weight (A) and mortality (B) of rats with acute lung injury;
FIG. 4 is a graph showing the effect of LH031 in combination with lidocaine on lung permeability (A) and lung factor (B) in rats with acute lung injury models;
FIG. 5 is a graph showing the effect of LH031 in combination with lidocaine on biochemical indicators of rats with acute lung injury models;
fig. 6 is a graph showing the effect of LH031 in combination with lidocaine on lung pathology scores in rats with acute lung injury models.
Detailed Description
For a better description of the objects, technical solutions and advantages of the present invention, the present invention will be further described with reference to the accompanying drawings and specific embodiments.
In the following examples, the experimental methods used are conventional methods unless otherwise specified, and the materials, reagents, etc. used are commercially available.
In the following examples, the structural formula of LH031 is shown in fig. 1. The structural formula of the lidocaine is shown in figure 2.
Example 1, LH031 in combination with lidocaine has therapeutic effect on acute lung injury in rats.
And (3) molding: 108 SPF-class SD rats of 8 weeks old, 200-220G, disinfecting the neck of the rats with iodine, making a longitudinal incision at the 1/3 central line position below the middle of the neck, exposing the lower edge of the thyroid gland and turning up, carefully separating and exposing the anterior tracheal muscle group, exposing the trachea by the longitudinal sharp separation muscle group, placing the animals at the high sole position of the head and the oblique foot, inserting 1mL of injector (26G) into the trachea at the position of about 2 tracheal rings below the annular cartilage ring, pushing 2mg/kg of LPS solution, taking a volume of 0.8mL/kg, observing that the nose has no bubble, and immediately rotating the rats vertically for 20s after pushing to ensure that the liquid medicine is evenly distributed in lung tissues and the medicine fully enters the lung. Placing animals obliquely at high and low positions, sewing incisions layer by layer, placing obliquely for 10min, and placing back into the squirrel cage.
Grouping: rats with successful model selection are randomly divided into 9 groups according to body weight, and each group comprises 12 rats, namely a normal control group, a model control group, a LH031 group, a lidocaine group and a LH 031+lidocaine group. The normal control group animals were tracheal-pushed with an equal volume of saline and the other procedures were the same as the model control group.
Administration: each group was given the corresponding test samples (dosing schedule is shown in table 1), 3 times per day, 1h after molding, 12h after molding, and 22h after molding, respectively; normal control group and model control group were given physiological saline.
TABLE 1
Detecting the index:
1. weight and mortality: body weight of each group of rats was measured 24 hours after molding, and mortality was recorded.
2. Lung coefficient measurement: after 24h molding, rats were sacrificed, lungs were removed and weighed, and lung coefficients were calculated: lung coefficient = lung weight/body weight 100%.
3. Lung permeability index determination: after the rats were sacrificed, serum specimens were left and their protein content was measured, and then alveolar lavage fluid was collected and its protein content was measured using coomassie brilliant blue, lung permeability index = bronchoalveolar lavage fluid protein/serum protein. The preparation method of the alveolar lavage fluid comprises the following steps: after the rat is anesthetized, the air tube is exposed, a 5mL disposable injector is selected, the needle is gently cut in from the 1/2 position of the air tube by tilting 30 degrees, then the air tube is horizontally inserted, the action is careful, the air tube is prevented from being punctured, the air tube and the needle are ligated at the tracheotomy, and the left thumb and the index finger of the operator press the joint of the needle and the air tube, so that the needle is prevented from sliding out. 5mL of sterile physiological saline was slowly injected into the bronchi at 1 minute intervals, and then the solution was withdrawn, and this was performed 3 times, and all lavage solutions were collected.
4. Detecting inflammatory factors: the content of TNF-alpha, IL-6 and IL-beta inflammatory factors in blood is detected by the kit.
5. Pathological morphology observation: after the animals are killed, the breast is opened by rapid surgical operation, the complete lung tissues are dissociated, after general observation is carried out by naked eyes, the part of the lung tissues at the same position are taken for paraformaldehyde fixation, the pathological changes are respectively considered from the inflammation degree, the alveolar wall thickening degree, the eosinophilic substances and the cell shedding degree by HE staining, and the lung injury is evaluated according to the pathological change degree: according to the degree of the lesion from light to heavy, marking 0 when the semi-quantitative is extremely small or no lesion is negative; mild or small "+" marks 1; medium or medium "++" is noted 2; severe or large amounts "+". ++'s 3, recording; extremely severe or massive "+++" "it is noted that in the case of the" 4 ", and counting the total score of each index score and analyzing.
And (3) data processing: experimental data were statistically processed by GraphPad Prism 7.0 biometric software: metering data are expressed in mean±sd and analyzed using two-way ANOVA in combination with Dunnett's multiple comparison method; analysis is carried out by adopting a variance analysis combined with Dunnett's multiple comparison method; the count data were analyzed using the Kruskal-Wallis rank sum test; analysis was performed using one-way ANOVA in combination with Dunnett's multiplex comparison.
Detection result:
1. general Condition observations and mortality
The animal state before molding is good, the animal can move freely, breathe uniformly, and the food intake is not obviously abnormal. The animal respiratory exacerbation, the respiratory sound is larger, even the situation of dyspnea of a few animals can appear after the animal modeling, which belongs to the normal expression after the animal modeling, and other abnormal expression is not found. There was no significant statistical difference (P > 0.05) in body weight for each treatment group after 24h of treatment compared to the model control group.
Mortality rate: after 24h of modeling and treatment, LH031 combined treatment with lidocaine showed efficacy in reducing mortality in animals with acute lung injury compared to model control, LH031 alone, and lidocaine alone (see table 2).
TABLE 2 Effect of LH031 in combination with lidocaine on mortality in acute lung injury rat model (N=12, mean.+ -. SD)
As is clear from Table 2, the mortality rate of rats was high when LH031 or lidocaine was administered alone, and when LH 031+lidocaine was used in combination, the mortality rate of animals suffering from acute lung injury was significantly reduced, which was better than that of animals suffering from acute lung injury when LH031 or lidocaine was administered alone (see FIG. 3), and in the present invention, the selection of the amounts of LH031 and lidocaine was important for the mortality rate of rats.
2. Lung coefficient and Lung permeability index determination
Compared with the normal control group, the lung coefficient and the lung permeability index of the model control group are obviously increased, and the statistical difference (P < 0.01) is provided, which indicates that the modeling is successful; compared with the model control group, the dosage of LH031 group reduces the lung coefficient and lung permeability index of the acute lung injury rat, and the reduction of the lung permeability index has statistical significance (P < 0.05); the lidocaine group slightly reduced the lung factor and lung permeability index in rats with acute lung injury, but was not statistically significant (P > 0.05). The combination of LH031 and lidocaine can obviously reduce the lung coefficient and the lung permeability index, has obvious statistical significance (P < 0.01), and is obviously superior to the single-use LH031 or the single-use lidocaine group (P <0.05 or 0.01), so that the combination of LH031 and lidocaine has a synergistic effect on reducing the lung coefficient and the lung permeability index of rats with acute lung injury. See table 3 and fig. 4.
TABLE 3 Effect of LH031 in combination with lidocaine on lung coefficients and lung permeabilities in rats model of acute lung injury (N=6, mean.+ -. SD)
Note that: in comparison with the model control group, * ：P<0.05； ** ：P<0.01; compared with LH031+ lidocaine group, # ：P<0.05；##：P<0.01。
3. blood index detection
The IL-1β, TNF- α, IL-6 levels were significantly elevated and statistically different (P < 0.01) in the model control group compared to the normal control group; the LH031 group decreased IL-1β, TNF- α, IL-6 levels (see Table 4), where IL-1β, TNF- α, IL-6 were statistically significant (P <0.05 or 0.01), compared to the model control group, indicating that LH031 treatment significantly decreased inflammatory factor (IL-1β, TNF- α, IL-6) levels in rats with acute lung injury; lidocaine group I also has a trend to decrease IL-1β, TNF- α, IL-6 levels, but only IL-1β is statistically significant (P < 0.05); LH 031+lidocaine combination can obviously reduce IL-1 beta, TNF-alpha and IL-6 levels, has obvious statistical significance (P < 0.01), and is obviously superior to LH031 or lidocaine group alone (P <0.05 or 0.01), so that LH 031+lidocaine combination has a synergistic effect on reducing the release of inflammatory factors of rats with acute lung injury (refer to figure 5).
TABLE 4 Effect of LH031 combination with lidocaine on the Biochemical index of acute lung injury model rats (N=12, mean.+ -. SD)
Note that: in comparison with the model control group, * ：P<0.05； ** ：P<0.01; compared with LH031+ lidocaine group, # ：P<0.05； ## ：P<0.01。
4. pathological morphology observation of lung tissue
Compared with the normal control group, the lung pathology score of the model control group is obviously increased, and the model control group has obvious statistical difference (P < 0.01), which indicates that the modeling is successful; the lung pathology score of LH031 group was reduced compared to model control group and had statistical significance (P < 0.05), indicating that LH031 treatment improved pathological changes in lung. The lung pathology score of the lidocaine group is reduced to a certain extent, but has no statistical significance (P is more than 0.05), and the lung pathology score of the combination group of LH031 and lidocaine is obviously reduced, and has obvious statistical significance (P < 0.01); meanwhile, the improvement of the LH 031+lidocaine combination on the lung pathology score of the rat is significantly better than that of the LH031 alone or the lidocaine group alone (P <0.05 or 0.01), which suggests that the LH 031+lidocaine combination has a synergistic effect on the improvement of the lung pathology score of the rat, and refer to FIG. 6.
Table 5 effect of LH031 in combination with lidocaine on acute lung injury model rat lung pathology score (n=6, mean±sd)
| Group of | Number of animals (Only) | Lung pathology scoring |
| |
6 | 4.67±1.72 |
| |
6 | 11.32±3.25 |
| LH031 set | 6 | 6.28±1.89 *# |
| |
6 | 8.57±2.43 ## |
| LH 031+ |
6 | 3.19±1.28 ** |
Note that: in comparison with the model control group, * ：P<0.05； ** ：P<0.01; compared with LH031+ lidocaine group, # ：P<0.05； ## ：P<0.01。
finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted equally without departing from the spirit and scope of the technical solution of the present invention.
Claims (6)
1. Use of a composition for the preparation of a medicament for the treatment of acute lung injury, wherein the composition comprises a compound and lidocaine; the structural formula of the compound is shown as a formula (I):
formula (I).
2. The use according to claim 1, wherein the dose of the compound is 1mg/kg to 40mg/kg.
3. The use according to claim 1, wherein the lidocaine concentration is 0.01% -0.1%.
4. The use according to claim 1, wherein the medicament is in the form of an oral or injectable formulation.
5. The use of claim 1, wherein the composition reduces lung factor, lung permeability index, inflammatory factors, and lung pathology score.
6. The use of claim 5, wherein the inflammatory factors comprise IL-1 β, TNF- α, and IL-6.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111372706.7A CN114191424B (en) | 2021-11-17 | 2021-11-17 | Pharmaceutical composition and application thereof in preparation of medicines for treating acute lung injury |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111372706.7A CN114191424B (en) | 2021-11-17 | 2021-11-17 | Pharmaceutical composition and application thereof in preparation of medicines for treating acute lung injury |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114191424A CN114191424A (en) | 2022-03-18 |
| CN114191424B true CN114191424B (en) | 2023-05-30 |
Family
ID=80648062
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111372706.7A Active CN114191424B (en) | 2021-11-17 | 2021-11-17 | Pharmaceutical composition and application thereof in preparation of medicines for treating acute lung injury |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114191424B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115364083B (en) * | 2022-08-26 | 2023-04-25 | 成都市第三人民医院 | Application of lidocaine derivative in preparation of product for preventing and treating intestinal barrier injury |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111514137A (en) * | 2020-04-14 | 2020-08-11 | 广州领晟医疗科技有限公司 | Application of compound in preparation of medicine for treating acute lung injury |
| CN111494392A (en) * | 2020-04-14 | 2020-08-07 | 广州领晟医疗科技有限公司 | Composition for treating acute lung injury and application thereof |
-
2021
- 2021-11-17 CN CN202111372706.7A patent/CN114191424B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN114191424A (en) | 2022-03-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Ettensohn et al. | Bronchoalveolar lavage in the normal volunteer subject: I. Technical aspects and intersubject variability | |
| Cohn et al. | Respiratory acidosis in patients with emphysema | |
| CN111514137A (en) | Application of compound in preparation of medicine for treating acute lung injury | |
| Nagase et al. | Tissue viscance during induced constriction in rabbit lungs: morphological-physiological correlations | |
| CN114191424B (en) | Pharmaceutical composition and application thereof in preparation of medicines for treating acute lung injury | |
| CN113876457A (en) | Economical, quantitative and noninvasive method for establishing mouse model for occupational disease of pulmonary fibrosis caused by silicon dust and preparation device | |
| CN105726572A (en) | Application of donkey-hide gelatins to preparation of medicament or healthcare product for treating respiratory injury caused by fine air particulate matters | |
| CN114794015A (en) | Construction method and application of lung injury animal model | |
| CN111494392A (en) | Composition for treating acute lung injury and application thereof | |
| Guidotti | Toxic inhalation of nitrogen dioxide: morphologic and functional changes | |
| Yang et al. | Study of the role of epidermal growth factor on lung fluid transport in rabbits with acute lung injury caused by endotoxin | |
| CN111820187A (en) | Method for establishing acute lung injury animal model | |
| CN111329870A (en) | Application of Yadanzigan in preparing medicine for treating and/or preventing lung injury | |
| CN114344343B (en) | Application of lactobacillus plantarum in preparation of acute lung injury resistant medicines | |
| WO2022236585A1 (en) | Use of hyaluronic acid in preparation of medication for treating pulmonary fibrosis | |
| CN114432421B (en) | KdPT polypeptide for treating acute lung injury and application thereof | |
| Kang et al. | A prospective, randomized comparison of the effects of inhaled sevoflurane anesthesia and propofol/remifentanil intravenous anesthesia on salivary excretion during laryngeal microsurgery | |
| WO2023097706A1 (en) | Application of polymerized hemoglobin in preparation of drug for preventing and treating respiratory failure | |
| CN113559100B (en) | Composition for treating lung injury and application thereof | |
| AU2020104218A4 (en) | Application of interleukin-37 in treating idiopathic pulmonary fibrosis | |
| Wong et al. | Pulmonary granulomatosis associated with insoluble fillers in a heroin addict | |
| CN113304249B (en) | Application of thymosin beta 4 in preparation of medicine for treating pulmonary fibrosis complicated with lung cancer | |
| CN108096242B (en) | Traditional Chinese medicine composition for treating chronic obstructive pulmonary disease | |
| CN115317505A (en) | Application of hyaluronic acid in preparation of medicament for treating pulmonary fibrosis | |
| Ejnell et al. | Laryngeal obstruction after Teflon injection |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |